We operate three clinical centers of the Diabetes Prevention Program (DPP), a multicenter randomized clinical trial of diabetes prevention in high-risk, but nondiabetic, adults. Nationally, the DPP enrolled 3,234 volunteers who received standard lifestyle recommendations and were randomly assigned to one of three interventions: intensive lifestyle with the aim of losing and maintaining 7% weight loss and achieving > 150 minutes per week of moderate intensity physical activity, metformin therapy with 850 mg twice per day, or placebo. The development of diabetes in the lifestyle intervention and metformin-treated groups were reduced by 58% and 31%, respectively, compared with the placebo group, during the first three years of treatment and follow-up. Many important issues remained unanswered, however. Specifically, whether the decrease in the development of diabetes can be sustained is unknown. Moreover, determining whether the delay or prevention of diabetes will translate into a decrease in retinopathy, nephropathy, neuropathy, and cardiovascular disease, all of which require more years to develop than the DPP period of study, is critical to establish the true impact of the DPP on public health. This long-term follow-up study of the DPP, the DPPOS, addresses these issues. Several findings were reported this fiscal year. Long-term weight loss with metformin or lifestyle intervention in the DPP. Identifying reliable predictors of long-term weight loss (LTWL) could lead to improved weight management. The DPP was a randomized controlled trial that compared weight loss with metformin, intensive lifestyle intervention (ILS), or placebo. Of the 3234 randomly assigned participants, 1066 lost at least 5% of baseline weight in the rst year and were followed for 15 years. After 1 year, 289 (28.5%) participants in the metformin group, 640 (62.6%) in the ILS group, and 137 (13.4%) in the placebo group had lost at least 5% of their weight. After the masked treatment phase ended, the mean weight loss relative to baseline that was maintained between years 6 and 15 was 6.2% in the metformin group, 3.7% in the ILS group, and 2.8% in the placebo group. Independent predictors of LTWL included greater weight loss in the rst year in all groups, older age and continued metformin use in the metformin group, older age and absence of either diabetes or a family history of diabetes in the ILS group, and higher fasting plasma glucose levels at baseline in the placebo group. In conclusion, among persons with weight loss of at least 5% after 1 year, those originally randomly assigned to metformin had the greatest loss during years 6 to 15. Older age and the amount of weight initially lost were the most consistent predictors of LTWL maintenance. Genetic ancestry markers and racial differences in HbA1c. HbA1c levels are higher in blacks than non-Hispanic whites (NHWs). We investigated whether genetics could explain this difference in Diabetes Prevention Program (DPP) participants. We tested (i) genetic variants causing hemoglobinopathies, (ii) a genetic risk score (GRS) based on 60 variants associated with HbA1c from genome-wide association meta-analysis, and (iii) principal component (PC) factors that capture continental ancestry derived from genetic markers distributed across the genome. Results: Of 2658 eligible DPP participants, 537 (20%) self-identified as black and 1476 (56%) as NHW. Despite comparable fasting and 2-hour glucose levels, blacks had higher HbA1c (mean = 6.2%) compared with NHWs (5.8%). In blacks, the genetic variant causing sickle cell trait was associated with higher HbA1c, by +0.44%. The GRS was associated with HbA1c in both blacks and NHWs. Self-identified blacks were distributed along the first PC axis, as expected in mixed ancestry populations. The first PC explained 60% of the 0.4% difference in HbA1c between blacks and NHWs, whereas the sickle cell variant explained 16% and GRS explained 14%. In conclusion, a large proportion of HbA1c difference between blacks and NHWs was associated with the first PC factor, suggesting that unidentified genetic markers influence HbA1c in blacks in addition to nongenetic factors. Diabetes prevention and long-term complications of diabetes. A variety of interventions, including lifestyle modifications and pharmacological agents directed at ameliorating the major risk factors for type 2 diabetes, are of proven efficacy in reducing the development of type 2 diabetes in people with impaired glucose regulation. While prevention of the hyperglycaemia characteristic of diabetes is arguably an important, clinically relevant out- come, a more compelling outcome with greater clinical significance is the prevention or reduction of the relatively diabetes-specific microvascular and less-specific cardiovascular disease (CVD) complications associated with diabetes. These complications cause the majority of morbidity and excess mortality associated with diabetes. Any reduction in diabetes should, logically, also reduce the occurrence of its long-term complications; however, most diabetes prevention trials have not been of sufficient duration to allow such an evaluation. The limited long-term data, largely from the Da Qing Diabetes Prevention Study (DQDPS) and the Diabetes Prevention Program (DPP) and their respective follow-up studies (DQDPOS and DPPOS), suggest a reduction in microvascular complications and amelioration of CVD risk factors. Only the DQDPOS and Study to Prevent Non-Insulin- Dependent Diabetes Mellitus (STOP-NIDDM) studies have shown a reduction in CVD events and only DQDPOS has demonstrated a decrease in CVD and overall mortality. While these limited data are promising, whether diabetes prevention directly reduces complication-related morbidity and mortality remains unclear. Longer follow-up of prevention studies is needed to supplement the limited current clinical trial data, to help differentiate the effects of diabetes prevention itself from the means used to reduce diabetes development and to understand the balance among benefits, risks and costs of prevention. Regression from impaired to normal glucose regulation and microvascular complications. Regression from impaired to normal glucose regulation (NGR) was associated with reduced incidence of diabetes by 56% over 10 years in participants in the DPPOS. In an observational analysis, we examined whether regression to NGR also reduced risk for microvascular disease (MVD) assessed at DPPOS year 11. Regression to NGR was associated with lower prevalence of aggregate MVD in models adjusted for age, sex, race/ethnicity, baseline HbA1c, and treatment arm (odds ratio OR =0.78). However, this association was lost in models that included average A1C during follow-up (OR=0.95) or diabetes at the end of follow-up (OR=0.92, 95% CI 0.75-1.12, P = 0.40). Similar results were observed in examination of the association between regression to NGR and prevalence of nephropathy and retinopathy, individually. Risk for aggregate MVD, nephropathy, and retinopathy increased across the A1C range. Regression to NGR is associated with a lower prevalence of aggregate MVD, nephropathy, and retinopathy, primarily due to lower glycemic exposure over time. Polygenic lipodystrophy genetic risk score. There is substantial heterogeneity in insulin sensitivity, and genetics may suggest possible mechanisms by which common variants influence this trait. We evaluated an 11-variant polygenic lipodystrophy genetic risk score (GRS) for association with anthropometric, glycemic and metabolic traits and CVD risk factors in the DPP. In secondary analyses, we tested the association of the GRS with cardiovascular risk factors in the DPP. In 2713 DPP participants, we evaluated the GRS of 11 common variants associated with fasting insulin-based measures of insulin sensitivity disc